Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma

Sci Rep. 2016 Jul 27:6:30486. doi: 10.1038/srep30486.

Abstract

The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased α-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to-α-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing α-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytoma / enzymology*
  • Astrocytoma / genetics*
  • Base Sequence
  • Binding Sites
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics*
  • Cell Line, Tumor
  • Glutarates / metabolism
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrates / metabolism
  • Mice
  • Mutation / genetics*
  • NADP / metabolism
  • Neoplasm Grading
  • Protein Multimerization

Substances

  • Glutarates
  • Isocitrates
  • alpha-hydroxyglutarate
  • NADP
  • isocitric acid
  • Isocitrate Dehydrogenase
  • IDH1 protein, human